Interactions between genetic and epidemiological factors influencing mammographic density

Suger AH, Chen H, Haas CB, Fan S, Scott CG, Bolla MK, Dennis J, Dunning AM, Michailidou K, Wang Q, Fasching P, Häberle L, Stone J, Gago-Dominguez M, Castelao JE, Murphy RA, Aronson K, Couch FJ, Yadav S, Milne RL, Hopper JL, Norman A, Eliassen AH, Tapper WJ, Eccles DM, Evans DG, Astley S, Hall P, Czene K, Pharoah PD, Antoniou AC, García-Closas M, Berrington A, Easton DF, Gierach GL, Tamimi RM, Vachon CM, Lindström S, Harrison TA (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 195

Pages Range: 1231-1241

Journal Issue: 5

DOI: 10.1093/aje/kwaf067

Abstract

Studies have identified genetic and epidemiologic factors associated with mammographic density (MD) phenotypes. However, MD-associated genetic variants only account for a small proportion of the total estimated heritability. Interrogating interactions between genetic and epidemiologic factors could potentially identify additional MD-associated loci, expand our understanding of the genetic basis of MD phenotypes, and clarify how epidemiologic factors modulate relationships between genetic variants and MD. We conducted six separate genome-wide, gene–environment (GxE) interaction analyses, applying 2 degrees of freedom (df) and 1df interaction tests, for each of three MD phenotypes (percent density, dense area (DA), and nondense area (NDA)). The six epidemiologic factors considered were height, ever parous, parity, ever menopausal hormone therapy, ever breastfeeding, and months of breastfeeding. We included European ancestry participants from multiple studies within the Markers of Density consortium and the Breast Cancer Association Consortium (n = 4895-16 218 depending on specific analyses). We identified 11 loci with genome-wide significant (P < 5 × 10⁻⁸) interaction tests including two novel common genetic signals interacting with parity (8p21.2) and ever breastfeeding (19p13.2) for NDA. Our results suggest that epidemiologic risk factors might influence relationships between common genetic variants and MD phenotypes at particular genomic loci.

Authors with CRIS profile

Involved external institutions

The Institute of Cancer Research (ICR) United Kingdom (GB) University of Cambridge United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) Weill Cornell Medicine United States (USA) (US) Mayo Clinic United States (USA) (US) University of Western Australia (UWA) Australia (AU) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) University of British Columbia Canada (CA) Queen's University Canada (CA) Cancer Council Victoria Australia (AU) Melbourne School of Population and Global Health Australia (AU) University of Manchester United Kingdom (GB) Karolinska Institute Sweden (SE) Cedars-Sinai Medical Center United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) University of Southampton United Kingdom (GB)

How to cite

APA:

Suger, A.H., Chen, H., Haas, C.B., Fan, S., Scott, C.G., Bolla, M.K.,... Harrison, T.A. (2026). Interactions between genetic and epidemiological factors influencing mammographic density. American Journal of Epidemiology, 195(5), 1231-1241. https://doi.org/10.1093/aje/kwaf067

MLA:

Suger, Austin Hammermeister, et al. "Interactions between genetic and epidemiological factors influencing mammographic density." American Journal of Epidemiology 195.5 (2026): 1231-1241.

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